This is a multifaceted Program consisting of four Projects designed to increase our understanding of the cellular and molecular feature of the monoclonal gammopathy in order to develop more effective therapy. The Program Project will expand our limited experience with long-term follow-up of patients with monoclonal gammopathy of undetermined significance (MGUS). Based upon our past experience, one-fourth of patients with an apparently benign monoclonal gammopathy will develop serious disease such as multiple myeloma, macroglobulinemia, amyloidosis, or related disorders over long- term follow-up. Two Cores are included: Core will centralize the collection of peripheral blood, serum and bone marrow from patients with monoclonal gammopathies, and Core 9007 will be responsible for all epidemiological, statistical, and data management aspects of the Program Project. Dr. Kyle, in Project I, will determine the prevalence of MGUS in Olmsted County. He will conduct a retrospective study of survival and risk of multiple myeloma, primary amyloidosis, and other plasma cell proliferative disorders that have been recognized in Southeastern Minnesota (including Olmsted County) from 1960 through 1994. In addition, he will follow all survivors of the Southeastern Minnesota MGUS cohort and all subsequently newly diagnosed cases in a prospective study to ascertain their outcomes. Bone marrow cells and serum will be collected through the Core A facility which will be critical for much of the subsequent research projects. Dr. Lust, in Project 2, will ascertain the role of IL-1beta and IL-6 in the progression of MGUS to multiple myeloma. He has demonstrated the existence of a novel IL-6 receptor (IL-6R) mRNA in myeloma cells that encodes a soluble form of the IL-6R. We propose to develop a soluble IL-6R that will inhibit IL-6 activity. In Project 3, Dr. Jelinek will ascertain the role of CD40 expression in myeloma cells and determine expression patterns of the natural ligand for CD40 in MGUS and myeloma patients. She will also determine the role of the product of the retinoblastoma gene (pRb1) in CD40 signalling and production of IL-6 and will characterize the expression of pRb1 in MGUS and myeloma patients. Drs. Van Ness and Witzig, in Project 4, will identify, quantitate, and characterize circulating plasma cells and clonally related cells in patients with MGUS and multiple myeloma using immunofluorescence microscopy, flow cytometry, and tumor- specific ASO-PCR techniques. They will also examine the ability of sorted populations of cells from myeloma patients to differentiate and expand in cytokine supplemented cultures in SCID mice. We anticipate that the studies proposed in this Program Project will clarify the molecular and cellular changes that occur in patients with benign monoclonal gammopathy prior to the development of multiple myeloma or related disorders. We hope this will lead to novel therapeutic strategies.